Is PRPF8 p.Asp1663Asn (c.4987G>A) pathogenic?

PRPF8 p.Asp1663Asn (c.4987G>A) is classified Uncertain significance in PRPF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). AlphaMissense: likely pathogenic (0.9926); Absent from gnomAD v4.1.

How common is PRPF8 p.Asp1663Asn (c.4987G>A) in the general population?

PRPF8 p.Asp1663Asn (c.4987G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRPF8 p.Asp1663Asn (c.4987G>A)?

AlphaMissense predicts likely pathogenic (score 0.9926) — an in-silico prediction, not a clinical call.

PRPF8 p.Asp1663Asn

c.4987G>A · rs2543729542 · VCV1996555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9926 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9926	likely pathogenic
REVEL	0.592	indeterminate
SaProt	LLR -10.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 1,244 bp · p 5e-12 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PRPF8
Protein: p.Asp1663Asn
Coding: c.4987G>A
MANE Select: NM_006445
dbSNP: rs2543729542
Type: single nucleotide variant
Location: chr17:1659508 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.20 · 100 PDB
Residue 1663: a β-strand; the 'restriction endonuclease homology domain' region

Full PRPF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRPF8 p.Arg1935His Pathogenic/Likely pathogenic ★★ same type
PRPF8 p.Arg2310Gly Pathogenic/Likely pathogenic ★★ same type
PRPF8 p.Arg2310Lys Pathogenic ★★ ⚠ same type
PRPF8 p.Arg2310Ser Pathogenic ★★ ⚠ same type
PRPF8 p.Gln2321Ter Pathogenic/Likely pathogenic ★★ same type
PRPF8 p.His2309Arg Pathogenic ★★ ⚠ same type
PRPF8 p.His2309Pro Pathogenic/Likely pathogenic ★★ same type
PRPF8 p.His2313Pro Likely pathogenic ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/prpf8-p-asp1663asn (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown